Application of kinetic model to in vitro percutaneous permeation of drugs

Abstract

Kinetic model using inter-compartmental rate constants, for permeation of drug across stratum corneum (k 1), for permeation across viable tissue layer of epidermis (k 2), and for back transfer of drug from viable tissue layer into the stratum corneum (k 3), was applied to in vitro percutaneous permeation process. Permeation data of four drugs, propranolol (PR), triamcinolone acetonide (TA), physostigmine (PHY), and tetrahydroaminoacridine (THA), previously studied across two skin membranes, hairless mouse skin (HMS) and human cadaver skin (HCS) were fitted to the permeation equation based on the kinetic model to obtain optimized values of the rate constants. The permeation profiles were also analyzed by the lag time method to estimate steady state flux (J ss), lag time (T lag), diffusion coefficient (D) and Skin/donor-phase partition coefficient (Km). The D and Km were used to regenerate the entire permeation profile (pre-steady and steady states) using equation based on Fick's laws of diffusion. The kinetic and diffusion models were compared by fits of the observed data to the model predicted values by linear regression, and obtaining R 2 and sum of squared deviations (SSD). Permeation data for all drugs across HMS or HCS, with or without the presence of permeation enhancer, were described very well by the kinetic model ( R 2 > 0.99), and the SSD's were smaller than that for the diffusion model except for THA. The rate of drug permeation across stratum corneum, k 0 (k 1 X Dose, amount of drug applied/cm 2 of skin in the donor phase) was similar to J ss as expected from the kinetic model. Diffusion coefficient of drug in the viable tissue (Dvt) ranged from 0.003–0.23 × 10 −7 cm 2/ s, similar to diffusion coefficient of similar sized molecules in protein gel as would be expected. Also, D vt was four orders of magnitude greater than D, the diffusion coefficient across stratum corneum, confirming stratum corneum to be the rate limiting barrier in the percutaneous permeation of the drugs studied. k 3 for all drugs were negligible indicating that no back diffusion of drug from viable tissue into the stratum corneum was occurring under the sink condition following infinite dose application. Also, except TA, none of the drug studied was lipophilic enough to be retained by the stratum corneum. Therefore, k 3 should not be used in the kinetic model for in vitro percutaneous permeation. For the PR 27-h, TA control and TA with 2% propylene glycol (PG) pretreatment experiments, the experiment duration was less than three T lag and steady state was not achieved, resulting in inaccurate estimates of D and Km and, hence, the regenerated profiles based on diffusion model did not describe the data well. However, kinetic model described these data also very well and SSD's were significantly smaller ( P = 0.05) than that for the diffusion model based regenerated profiles. The kinetic model is an alternative to diffusion model to describe the percutaneous permeation process, and the results presented here demonstrate the usefulness of the kinetic approach.